US4091099A - 6-Hydrocarbon-ergopeptines - Google Patents
6-Hydrocarbon-ergopeptines Download PDFInfo
- Publication number
- US4091099A US4091099A US05/645,568 US64556875A US4091099A US 4091099 A US4091099 A US 4091099A US 64556875 A US64556875 A US 64556875A US 4091099 A US4091099 A US 4091099A
- Authority
- US
- United States
- Prior art keywords
- dihydro
- compound
- isopropyl
- ergopeptine
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/02—Ergot alkaloids of the cyclic peptide type
Definitions
- the present invention relates to 9,10-dihydro-ergopeptines
- the present invention provides compounds of formula I, ##STR2## wherein R 1 is hydrogen, alkyl of 2 to 8 carbon atoms, or phenylalkyl of 7 to 9 carbon atoms, and
- R 2 is branched alkyl of 3 or 4 carbon atoms or benzyl.
- the present invention provides a process for the production of a compound of formula I, as defined above, which comprises condensing a reactive functional derivative of an acid of formula II, ##STR3## wherein R 1 is as defined above, WITH A COMPOUND OF FORMULA III, ##STR4## wherein R 2 is as defined above, IN ACID ADDITION SALT FORM.
- the process is a conventional condensation process for the production of peptide lysergic acid amides.
- reactive functional derivatives may be used the acid chloride hydrochloride, the acid azide or a mixed anhydride of an acid of formula II with sulphuric acid or trifluoroacetic acid.
- the reactive functional derivative is a reaction product of an acid of formula II and an amide chloride produced by reacting a chlorinating agent and a N-di(lower)alkyl substituted acid amide of a lower aliphatic carboxylic acid.
- chlorinating agent may be used phosgene or oxalyl chloride.
- phosgene or oxalyl chloride for the preparation of the amide chloride preferred amides are for example dimethyl formamide or dimethyl acetamide.
- the compound of formula III is preferably used in the form of the hydrochloride.
- R 1 is preferably alkyl of 2 to 4 carbon atoms, especially ethyl, n-propyl, iso-propyl, or iso-butyl.
- R 2 is preferably iso-propyl or sec.-butyl.
- Free base forms of compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa.
- Suitable acids for salt formation include hydrochloric acid.
- the compounds of formula I are useful because they possess pharmacological activity in animals.
- the compounds of formula I are useful as hypertonic agents, as indicated by standard tests.
- a pressor effect is observed in the spinal cat preparation on administration i.v. of from about 0.001 to about 1 mg/kg animal body weight of the compounds.
- an increase in the peripheral vascular resistance is observed in the autoperfused cat calf muscle (Mellander Cat preparation) on administration i.a. of from about 5 to about 60 ⁇ g/kg muscle of the compounds.
- the compounds of formula I are useful as agents for the treatment and prophylaxis of migraine, as indicated by standard tests.
- a serotonin antagonism is observed in the isolated rat uterus test using concentrations of from about 0.5 to about 15 mg/liter of the compounds.
- the compounds of formula I are useful as agents for the treatment of orthostatic disorders, as indicated by the pressor effect in the above-mentioned test. Additionally, this indication is confirmed by a tonisation of the capacity vessels in the above-mentioned cat test.
- the dosage will, of course, vary depending on the compound employed, mode of administration and therapy desired. However, in general, satisfactory results are obtained when administered at a daily dosage of from 0.001 mg to about 2 mg per kg animal body weight, conveniently given in divided doses 2 to 4 times a day or in sustained release form.
- the total daily dosage is in the range from about 1 to about 100 mg
- dosage forms suitable for oral administration comprise from about 0.2 mg to about 50 mg of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.
- a suitable dose range for all animals is from ca. 0.01 to ca. 0.5 mg/kg.
- a suitable daily dose is from ca. 1.5 mg to 30 mg preferably administered in daily doses of from about 0.75 to 10 mg.
- the Example 1 compound is the most interesting compound.
- the compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form.
- Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily prepared in conventional manner.
- the present invention also provides a pharmaceutical composition comprising a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
- Such compositions may be formulated so as to be, for example, a solution or a tablet.
- acids for acid addition salt formation include methane-sulphonic acid, fumaric acid, hydrobromic acid, malic acid.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
This invention provides new compounds of formula I, ##STR1## wherein R1 is hydrogen, alkyl of 2 to 8 carbon atoms, or phenylalkyl of 7 to 9 carbon atoms, and
R2 is branched alkyl of 3 or 4 carbon atoms or benzyl,
Useful as agents for the treatment of migraine, hypotonia and orthostatic disorders.
Description
The present invention relates to 9,10-dihydro-ergopeptines
The present invention provides compounds of formula I, ##STR2## wherein R1 is hydrogen, alkyl of 2 to 8 carbon atoms, or phenylalkyl of 7 to 9 carbon atoms, and
R2 is branched alkyl of 3 or 4 carbon atoms or benzyl.
The present invention provides a process for the production of a compound of formula I, as defined above, which comprises condensing a reactive functional derivative of an acid of formula II, ##STR3## wherein R1 is as defined above, WITH A COMPOUND OF FORMULA III, ##STR4## wherein R2 is as defined above, IN ACID ADDITION SALT FORM.
The process is a conventional condensation process for the production of peptide lysergic acid amides.
Reaction conditions are well known in ergot chemistry. Suitable reactive functional derivatives which can be used for the compounds of formula II are also known. The process may be effected in analogous manner to that described in Example 1.
As reactive functional derivatives may be used the acid chloride hydrochloride, the acid azide or a mixed anhydride of an acid of formula II with sulphuric acid or trifluoroacetic acid. Preferably the reactive functional derivative is a reaction product of an acid of formula II and an amide chloride produced by reacting a chlorinating agent and a N-di(lower)alkyl substituted acid amide of a lower aliphatic carboxylic acid.
As chlorinating agent may be used phosgene or oxalyl chloride. For the preparation of the amide chloride preferred amides are for example dimethyl formamide or dimethyl acetamide.
The compound of formula III is preferably used in the form of the hydrochloride.
Of the acids of formula II those wherein R1 is hydrogen or straight chain alkyl of 2 to 6 carbon atoms are known [Die Mutterkornalkaloide (1964), page 67 (A. Hofmann)]. The remaining acids of formula II may be produced analogous to 6-nor-6-ethyl-9,10-dihydro-lysergic acid [see Helv. Chim. Acta 53, 2197 f (1970)].
The compounds of formula III are known [Helv. Chim. Acta 52, 1549 f (1969)].
R1 is preferably alkyl of 2 to 4 carbon atoms, especially ethyl, n-propyl, iso-propyl, or iso-butyl.
R2 is preferably iso-propyl or sec.-butyl.
The compounds of formula I are named herein based on the following moiety of formula IV, ##STR5## which is called ergopeptine.
Insofar as the production of any starting material is not particularly described these compounds are known, or may be produced and purified in accordance with known processes, or in a manner analogous to processes described herein, e.g. in the Examples, or to known processes.
Free base forms of compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids for salt formation include hydrochloric acid.
In the following Examples all temperatures are in degrees Centigrade and are uncorrected.
8.6 cc (100 millimol) of oxalyl chloride dissolved in 20 cc of acetonitrile are added dropwise within 10 minutes to a solution of 300 cc of dimethyl formamide and 150 cc of acetonitrile at -10° to -15° and stirring is effected for 10 minutes. 29.8 g (100 millimol) of anhydrous 6-nor-6-isopropyl-9,10-dihydro-lysergic acid are added at -20°. The mixture is stirred for 30 minutes at -10°. Upon cooling to -20°, 200 cc of pyridine and 17.4 g (50 millimol) of (2R,5S,10aS,10bS)-2-amino-2,5-diisopropyl-3,6-dioxo-10b-hydroxy-octahydro-8H-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazine hydrochloride are added and the mixture is stirred for 2 hours at 0°. Working up is effected by adding 100 cc of buffer solution of pH 4 and the reaction mixture is distributed between methylene chloride and 2N caustic soda solution. The organic phases are washed twice with water, dried over sodium sulphate and evaporated to dryness at the rotavapor. The resulting crude base is dried in a high vacuum, is dissolved in ethanol in order to crystallize and the solution was inoculated. The title compound is obtained having a M.P. of 180° (decomposition); [α]D 20 = -8.7° (c = 1.046 in methanol).
In a manner analogous to Example 1, the following compounds may be produced:
______________________________________
Ex. Compound of Starting
No. formula I materials M.P. [α].sub.D.sup.20
______________________________________
2 6-nor-6-ethyl-9,10-
28.4 g 6-nor-6-
177-
dihydro-2'β,5'α-di-
ethyl-9,10-di-
178°
- 11.8°
isopropyl-ergo-
hydro-lysergic
(de- (c = 0.518
peptine acid and comp.)
in CH.sub.3 OH)
17.4 g A*
3 6-nor-6-isopropyl-
29.8 g 6-nor-6-
221°
9,10-dihydro-2'β,
isopropyl-9,10-
(de- - 30.1°
5'α-diisopropyl-
dihydro-lysergic
comp.)
(c = 0.466
ergopeptine acid and in CH.sub.3 OH)
17.4 g A*
4 6-nor-6-n-butyl-
31.2 g 6-nor-6-
170-
9,10-dihydro-2'β,
n-butyl-9,10-
171°
- 10.7°
5'α-diisopropyl-
dihydro-lysergic
(de- (c = 1.025
ergopeptine acid and comp.)
in CH.sub.3 OH)
17.4 g A*
5 6-nor-6-isobutyl-
31.2 g 6-nor-6-
191°
9,10-dihydro-2'β,
isobutyl-9,10-
(de- - 22.0°
5'α-diisopropyl-
dihydro-lysergic
comp.)
(c = 1.005
ergopeptine acid and in CH.sub.3 OH)
17.4 g A*
6 6-nor-6-isopentyl-
32.6 g 6-nor-6-
164- - 14.2°
9,10-dihydro-2'β,
isopentyl-9,10-
166°
(c = 1.032
5'α-diisopropyl-
dihydro-lysergic
(de- in CH.sub.3 OH)
ergopeptine acid and comp.)
17.4 g A
7 6-nor-6-n-hexyl-
34.0 g 6-nor-6-
216°
9,10-dihydro-2'β,
n-hexyl-9,10-
(de- - 15.2°
5'α-diisopropyl-
dihydro-lysergic
comp.) (c = 1.043
ergopeptine acid and in CH.sub.3 OH)
17.4 g A*
8 6-nor-6-phenethyl-
36.9 g 6-nor-6-
210°
9,10-dihydro-2'β,
phenethyl-9,10-
(de- -6.4°
5'α-diisopropyl-
dihydro-lysergic
comp.)
(c = 0.740
ergopeptine acid and in CH.sub.3 OH
17.4 g A*
9 6-nor-6-isopropyl-
29.8 g 6-nor-6-
211°
9,10-dihydro-2'β-
isopropyl-9,10-
(de- - 9.1°
isopropyl-5'α-sec.
dihydro-lysergic
comp.)
(c = 0.811
butyl-ergopeptine
acid and 18.1 g in CH.sub.3 OH)
B**
10 6-nor-6-n-butyl-9,10
31.2 g 6-nor-6-
186-
dihydro-2'β-iso-
butyl-9,10-di-
187°
- 8.7°
propyl-5'α-sec.-
hydro-lysergic
(de- (c = 1.0
butyl-ergopeptine
acid and comp.)
in CH.sub.2 Cl.sub.2)
18.1 g B**
11 6-nor-6-isopentyl-
32.6 g 6-nor-6-
221°
9,10-dihydro-2'β-
isopentyl-9,10-
(de- - 10.9°
isopropyl-5'α-sec.
dihydro-lysergic
comp.)
(c = 1.048
butyl-ergopeptine
acid and in CH.sub.2 Cl.sub.2)
18.1 g B**
12 6-nor-9,10-dihydro-
25.6 g 6-nor-
192°
2'β-isopropyl-5'α-
9,10-dihydro-
(de- + 9.2°
benzyl-ergopentine
lysergic acid
comp.)
(c = 0.978
and 19.8 g C*** in
dimethyl-
sulphoxide)
13 6-nor-6-isobutyl-
31.2 g 6-nor-6-
198-
9,10-dihydro-2'β-
isobutyl-9,10-
199°
-0 34.3°
isopropyl-5-'α-benzyl
dihydro-lysergic
(de- (c = 0.968
ergopeptine acid and 19.8 g
comp.)
in CH.sub.2 Cl.sub.2)
C***
______________________________________
*A =
(2R,5S,10aS,10bS)-2-amino-2,5-di-isopropyl-3,6-dioxo-10b-hydroxy-octahydr
-8H-oxazolo[3,2-a] pyrrolo[2,1-c]pyrazine-hydrochloride
**B =
(2R,5S,10aS,10bS)-2-amino-2-iso-propyl-5-sec.-butyl-3,6-dioxo-10b-hydroxy
octahydro-8H-oxazolo-[3,2-a]pyrrolo[2,1-c]pyrazine-hydrochloride
***C =
(2R,5S,10aS,10bS)-2-amino-2-iso-propyl-5-benzyl-3,6-dioxo-10b-hydroxy-oct
hydro-8H-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazine-hydrochloride
The compounds of formula I have not been described in the literature.
The compounds of formula I are useful because they possess pharmacological activity in animals. In particular, the compounds of formula I are useful as hypertonic agents, as indicated by standard tests.
For example a pressor effect is observed in the spinal cat preparation on administration i.v. of from about 0.001 to about 1 mg/kg animal body weight of the compounds. Additionally, a blocking effect on the α-adrenergic receptors in the isolated seminal vesicle of the guinea pig using concentrations of from about 1 × 10-9 to about 1 × 10-6 g/ml of the compounds. Furthermore an increase in the peripheral vascular resistance is observed in the autoperfused cat calf muscle (Mellander Cat preparation) on administration i.a. of from about 5 to about 60 μg/kg muscle of the compounds.
Furthermore the compounds of formula I are useful as agents for the treatment and prophylaxis of migraine, as indicated by standard tests. For example a serotonin antagonism is observed in the isolated rat uterus test using concentrations of from about 0.5 to about 15 mg/liter of the compounds.
Furthermore, the compounds of formula I are useful as agents for the treatment of orthostatic disorders, as indicated by the pressor effect in the above-mentioned test. Additionally, this indication is confirmed by a tonisation of the capacity vessels in the above-mentioned cat test.
For all the above mentioned use the dosage will, of course, vary depending on the compound employed, mode of administration and therapy desired. However, in general, satisfactory results are obtained when administered at a daily dosage of from 0.001 mg to about 2 mg per kg animal body weight, conveniently given in divided doses 2 to 4 times a day or in sustained release form. For the larger mammal, the total daily dosage is in the range from about 1 to about 100 mg, and dosage forms suitable for oral administration comprise from about 0.2 mg to about 50 mg of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.
In an Example a suitable dose range for all animals is from ca. 0.01 to ca. 0.5 mg/kg. For the larger mammal a suitable daily dose is from ca. 1.5 mg to 30 mg preferably administered in daily doses of from about 0.75 to 10 mg.
The Example 1 compound is the most interesting compound.
The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be formulated so as to be, for example, a solution or a tablet.
Further acids for acid addition salt formation include methane-sulphonic acid, fumaric acid, hydrobromic acid, malic acid.
Claims (15)
1. A compound of formula I, ##STR6## wherein R1 is isopropyl, isobutyl, isopentyl or phenethyl, and
R2 is branched alkyl of 3 or 4 carbon atoms or benzyl,
in free base form or in pharmaceutically acceptable acid addition salt form.
2. A compound of claim 1, wherein R2 is isopropyl, iso- or sec.-butyl or benzyl.
3. A compound of claim 1, wherein R2 is isopropyl or sec.-butyl.
4. A pharmaceutical composition for use in the treatment of hypotonia, orthostatic disorders or migraine comprising an effective amount of a compound of claim 1 in association with a pharmaceutical carrier or diluent.
5. A method of treating hypotonia, orthostatic disorders or migraine in an animal in need of said treatment comprising administering a therapeutically effective amount of a compound of claim 1.
6. The compound according to claim 1 which is 6-nor-6-isopropyl-9,10-dihydro-2'β, 5'α-diisopropyl-ergopeptine.
7. The compound according to claim 1 which is 6-nor-6-isobutyl-9,10-dihydro-2'β, 5'α-diisopropyl-ergopeptine.
8. The compound according to claim 1 which is 6-nor-6-isopentyl-9,10-dihydro-2'β, 5'β-diisopropyl-ergopeptine.
9. The compound according to claim 1 which is 6-nor-6-phenethyl-9,10-dihydro-2'β, 5'α-diisopropyl-ergopeptine.
10. The compound according to claim 1 which is 6-nor-6-isopropyl-9,10-dihydro-2'β-isopropyl-5'α-sec. butyl-ergopeptine.
11. The compound according to claim 1 which is 6-nor-6-isopentyl-9,10-dihydro-2'β-isopropyl-5'α-sec. butyl-ergopeptine.
12. The compound according to claim 1 which is 6-nor-6-isobutyl-9,10-dihydro-2'β-isopropyl-5'α-benzyl ergopeptine.
13. A pharmaceutical composition according to claim 4, comprising 0.2 to 50 milligrams per unit dosage.
14. A method according to claim 5 in which 1 to 100 milligrams of the compound are administered daily.
15. A method according to claim 14 in which 0.2 to 50 milligrams of the compound are administered per unit dosage.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH68/75 | 1975-01-06 | ||
| CH6875A CH601321A5 (en) | 1975-01-06 | 1975-01-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4091099A true US4091099A (en) | 1978-05-23 |
Family
ID=4178558
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US05/645,568 Expired - Lifetime US4091099A (en) | 1975-01-06 | 1975-12-31 | 6-Hydrocarbon-ergopeptines |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US4091099A (en) |
| JP (1) | JPS5191299A (en) |
| BE (1) | BE837312A (en) |
| CH (1) | CH601321A5 (en) |
| DE (1) | DE2557792A1 (en) |
| FR (1) | FR2296419A1 (en) |
| GB (1) | GB1529251A (en) |
| NL (1) | NL7600002A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4145549A (en) * | 1976-01-12 | 1979-03-20 | Sandoz Ltd. | Process for preparing oxazolo 3,2-a!pyrrolo 2,1-c!pyrazine derivatives |
| US4229451A (en) * | 1973-11-28 | 1980-10-21 | Sandoz Ltd. | Ergopeptine derivatives |
| US4547500A (en) * | 1979-06-12 | 1985-10-15 | Sandoz Ltd. | Ergot peptide derivatives, their preparation and pharmaceutical compositions containing them |
| US4654345A (en) * | 1984-10-24 | 1987-03-31 | Sandoz Ltd. | Occular formulation comprising bromocriptine |
| US4737499A (en) * | 1982-02-12 | 1988-04-12 | Sandoz Ltd. | Ergotalkaloids for treating senile dementia |
| US5069911A (en) * | 1985-02-05 | 1991-12-03 | Sandoz Ltd. | Pharmaceutical 9,10-dihydrogenated ergot alkaloid containing compositions |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB769260A (en) | 1954-04-07 | 1957-03-06 | Sandoz Ltd | Process for the preparation of isomeric racemic dihydrolysergic acids and their homologues |
| US3586683A (en) * | 1967-04-12 | 1971-06-22 | Sandoz Ltd | 2,5(5) - di(tri)substituted - 10b-hydroxy-3,6 - dioxo-octahydro-oxazolo(3,2-a) pyrrolo(2,1-c)pyrazine derivatives of lysergic acid |
| US3652569A (en) * | 1967-08-02 | 1972-03-28 | Sandoz Ltd | Ergonine ergoptine and the 1-methyl and 9 10-dihydro derivatives thereof |
| US3920664A (en) * | 1972-07-21 | 1975-11-18 | Lilly Co Eli | D-2-halo-6-alkyl-8-substituted ergolines and related compounds |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1301346A (en) * | 1969-05-06 | 1972-12-29 | ||
| CH587858A5 (en) * | 1973-11-28 | 1977-05-13 | Sandoz Ag | |
| DE2525962A1 (en) * | 1974-06-21 | 1976-01-08 | Sandoz Ag | NEW HETEROCYCLIC COMPOUNDS, THEIR PRODUCTION AND USE |
-
1975
- 1975-01-06 CH CH6875A patent/CH601321A5/xx not_active IP Right Cessation
- 1975-12-22 DE DE19752557792 patent/DE2557792A1/en active Pending
- 1975-12-31 US US05/645,568 patent/US4091099A/en not_active Expired - Lifetime
-
1976
- 1976-01-02 NL NL7600002A patent/NL7600002A/en not_active Application Discontinuation
- 1976-01-02 GB GB51/76A patent/GB1529251A/en not_active Expired
- 1976-01-05 BE BE163314A patent/BE837312A/en unknown
- 1976-01-05 JP JP51000047A patent/JPS5191299A/ja active Pending
- 1976-01-06 FR FR7600132A patent/FR2296419A1/en active Granted
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB769260A (en) | 1954-04-07 | 1957-03-06 | Sandoz Ltd | Process for the preparation of isomeric racemic dihydrolysergic acids and their homologues |
| US3586683A (en) * | 1967-04-12 | 1971-06-22 | Sandoz Ltd | 2,5(5) - di(tri)substituted - 10b-hydroxy-3,6 - dioxo-octahydro-oxazolo(3,2-a) pyrrolo(2,1-c)pyrazine derivatives of lysergic acid |
| US3652569A (en) * | 1967-08-02 | 1972-03-28 | Sandoz Ltd | Ergonine ergoptine and the 1-methyl and 9 10-dihydro derivatives thereof |
| US3920664A (en) * | 1972-07-21 | 1975-11-18 | Lilly Co Eli | D-2-halo-6-alkyl-8-substituted ergolines and related compounds |
Non-Patent Citations (1)
| Title |
|---|
| Merck Index, 8th edition, p. 14, (1968). * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4229451A (en) * | 1973-11-28 | 1980-10-21 | Sandoz Ltd. | Ergopeptine derivatives |
| US4145549A (en) * | 1976-01-12 | 1979-03-20 | Sandoz Ltd. | Process for preparing oxazolo 3,2-a!pyrrolo 2,1-c!pyrazine derivatives |
| US4547500A (en) * | 1979-06-12 | 1985-10-15 | Sandoz Ltd. | Ergot peptide derivatives, their preparation and pharmaceutical compositions containing them |
| US4737499A (en) * | 1982-02-12 | 1988-04-12 | Sandoz Ltd. | Ergotalkaloids for treating senile dementia |
| US4654345A (en) * | 1984-10-24 | 1987-03-31 | Sandoz Ltd. | Occular formulation comprising bromocriptine |
| US5069911A (en) * | 1985-02-05 | 1991-12-03 | Sandoz Ltd. | Pharmaceutical 9,10-dihydrogenated ergot alkaloid containing compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5191299A (en) | 1976-08-10 |
| FR2296419B1 (en) | 1979-06-29 |
| CH601321A5 (en) | 1978-07-14 |
| DE2557792A1 (en) | 1976-07-08 |
| GB1529251A (en) | 1978-10-18 |
| FR2296419A1 (en) | 1976-07-30 |
| BE837312A (en) | 1976-07-05 |
| NL7600002A (en) | 1976-07-08 |
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